Genomic Structural Variants pp 29-75

Part of the Methods in Molecular Biology book series (MIMB, volume 838)

Microdeletion and Microduplication Syndromes

Abstract

During the past decade, widespread use of microarray-based technologies, including oligonucleotide array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) genotyping arrays have dramatically changed our perspective on genome-wide structural variation. Submicroscopic genomic rearrangements or copy-number variation (CNV) have proven to be an important factor responsible for primate evolution, phenotypic differences between individuals and populations, and susceptibility to many diseases. The number of diseases caused by chromosomal microdeletions and microduplications, also referred to as genomic disorders, has been increasing at a rapid pace. Microdeletions and microduplications are found in patients with a wide variety of phenotypes, including Mendelian diseases as well as common complex traits, such as developmental delay/intellectual disability, autism, schizophrenia, obesity, and epilepsy. This chapter provides an overview of common microdeletion and microduplication syndromes and their clinical phenotypes, and discusses the genomic structures and molecular mechanisms of formation. In addition, an explanation for how these genomic rearrangements convey abnormal phenotypes is provided.

Key words

Copy-number variation Recurrent and nonrecurrent genomic rearrangements Contiguous gene deletion/duplication syndrome Higher-order genomic structure NAHR NHEJ MMBIR DNA microhomology Genomic disorders 

References

  1. 1.
    Lupski, J.R. (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14, 417–22.PubMedGoogle Scholar
  2. 2.
    Lupski, J.R. (2009) Genomic disorders ten years on. Genome Med 24, 1–42.Google Scholar
  3. 3.
    Pinkel, D., Segraves, R., Sudar, D., Clark, S., Poole, I., Kowbel, D., Collins, C., Kuo, W.-L., Chen, C., Zhai, Y., Dairkee, S.H., Ljung, B.M., Gray, J.W., Albertson, D.G. (1998) High resolution analysis of DNA copy-number variation using comparative genomic hybridization to microarrays. Nat Genet 20, 207–11.PubMedGoogle Scholar
  4. 4.
    Solinas-Toldo, S., Lampel, S., Stilgenbauer, S., Nickolenko, J., Benner, A., Dohner, H., Cremer, T., Lichter, P. (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20, 399–407.PubMedGoogle Scholar
  5. 5.
    Iafrate, A.J., Feuk, L., Rivera, M.N., Listewnik, M.L., Donahoe, P.K., Qi, Y., Scherer, S.W., Lee, C. (2004) Detection of large-scale variation in the human genome. Nat Genet 36, 949–51.PubMedGoogle Scholar
  6. 6.
    Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Månér, S., Massa, H., Walker, M., Chi, M., Navin, N., Lucito, R., Healy, J., Hicks, J., Ye, K., Reiner, A., Gilliam, T.C., Trask, B., Patterson, N., Zetterberg, A., Wigler, M. (2004) Large-scale copy-number polymorphism in the human genome. Science 305, 525–8.PubMedGoogle Scholar
  7. 7.
    Redon, R., Ishikawa, S., Fitch, K.R., Feuk, L., Perry, G.H., Andrews, T.D., Fiegler, H., Shapero, M.H., Carson, A.R., Chen, W., Cho, E.K., Dallaire, S., Freeman, J.L., González, J.R., Gratacòs, M., Huang, J., Kalaitzopoulos, D., Komura, D., MacDonald, J.R., Marshall, C.R., Mei, R., Montgomery, L., Nishimura, K., Okamura, K., Shen, F., Somerville, M.J., Tchinda, J., Valsesia, A., Woodwark, C., Yang, F., Zhang, J., Zerjal, T., Zhang, J., Armengol, L., Conrad, D.F., Estivill, X., Tyler-Smith, C., Carter, N.P., Aburatani, H., Lee, C., Jones, K.W., Scherer, S.W., Hurles, M.E. (2006) Global variation in copy-number in the human genome. Nature 444, 444–54.PubMedGoogle Scholar
  8. 8.
    Stankiewicz, P., Beaudet, A.L. (2007) Use of arrayCGHin the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 17, 182–92.PubMedGoogle Scholar
  9. 9.
    Slavotinek, A.M. (2008) Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet 124, 1–17.PubMedGoogle Scholar
  10. 10.
    Stankiewicz, P., Lupski, J.R. (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61, 437–55.PubMedGoogle Scholar
  11. 11.
    Carvalho, C.M.B., Zhang, F., Lupski JR. (2010) Evolution in Health and Medicine Sackler Colloquium: Genomic disorders: A window into human gene and genome evolution. PNAS 107, 1765–71.PubMedGoogle Scholar
  12. 12.
    Stankiewicz, P., Lupski, J.R. (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18, 74–82.PubMedGoogle Scholar
  13. 13.
    Bailey, J.A., Yavor, A.M., Massa, H.F., Trask, B.J., Eichler, E.E. (2001) Segmental duplications: organization and impact within the current Human Genome Project assembly. Genome Res 11, 1005–17.PubMedGoogle Scholar
  14. 14.
    Eichler, E.E. (2001) Recent duplication, domain accretion and the dynamic mutation of the human genome. Trends Genet 17, 661–9.PubMedGoogle Scholar
  15. 15.
    Slack, A., Thornton, P.C., Magner, D.B., Rosenberg, S.M., Hastings, P.J. (2006) On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet 2, e48.PubMedGoogle Scholar
  16. 16.
    Lee, J.A., Carvalho, C.M., Lupski, J.R. (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131, 1235–47.PubMedGoogle Scholar
  17. 17.
    Hastings, P.J., Ira, G., Lupski, J.R. (2009) A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5, e1000327.PubMedGoogle Scholar
  18. 18.
    Schmickel, R.D. (1986) Contiguous gene syndromes: a component of recognizable syndromes. J Pediatr 109, 231–41.PubMedGoogle Scholar
  19. 19.
    Katsanis, N., Ansley, S.J., Badano, J.L., Eichers, E.R., Lewis, R.A., Hoskins, B.E., Scambler, P.J., Davidson, W.S., Beales, P.L., Lupski, J.R. (2001) Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293, 2256–9.PubMedGoogle Scholar
  20. 20.
    Zhang F, Gu W, Hurles ME, Lupski JR. (2009) Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 10, 451–81.Google Scholar
  21. 21.
    Firth, H.V., Richards, S.M., Bevan, A.P., Clayton, S., Corpas, M., Rajan, D., Van Vooren, S., Moreau, Y., Pettett, R.M., Carter, N.P. (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 84, 524–33.PubMedGoogle Scholar
  22. 22.
    Pfeiffer, P., Goedecke, W., Obe, G. (2000) Mechanisms of DNA double-strand break repair and their potential to induce chromosomal aberrations. Mutagenesis 15, 289–302.PubMedGoogle Scholar
  23. 23.
    Zhang, F., Khajavi, M., Connolly, A.M., Towne, C.F., Batish, S.D., Lupski, J.R. (2009) The DNA replication FoSTeS/MMBIR mechanism can generate human genomic, genic, and exonic complex rearrangements. Nat Genet 41, 849–53.PubMedGoogle Scholar
  24. 24.
    Carvalho, C.M., Zhang, F., Liu, P., Patel, A., Sahoo, T., Bacino, C.A., Shaw, C., Peacock, S., Pursley, A., Tavyev, Y.J., Ramocki, M.B., Nawara, M., Obersztyn, E., Vianna-Morgante, A.M., Stankiewicz, P., Zoghbi, H.Y., Cheung, S.W., Lupski, J.R. (2009) Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet 18, 2188–203.PubMedGoogle Scholar
  25. 25.
    Bi, W., Sapir, T., Shchelochkov, O.A., Zhang, F., Withers, M.A., Hunter, J.V., Levy, T., Shinder, V., Peiffer, D.A., Gunderson, K.L., Nezarati, M.M., Shotts, V.A., Amato, S.S., Savage, S.K., Harris, D.J., Day-Salvatore, D.L., Horner, M., Lu, X.Y., Sahoo, T., Yanagawa, Y., Beaudet, A.L., Cheung, S.W., Martinez, S., Lupski, J.R., Reiner, O. (2008) LIS1 increased expression affects human and mouse brain development. Nat Genet 41, 168–77.Google Scholar
  26. 26.
    Nagamani, S.C.S., Zhang, F., Shchelochkov, O.A., Bi, W., Ou, Z., Scaglia, F., Probst, F.J., Shinawi, M., Eng, C., Hunter, J.V., Sparagana, S., Lagoe, E., Fong, C.T., Pearson, M., Doco-Fenzy, M., Landais, E., Mozelle, M., Chinault, A.C., Patel, A., Bacino, C.A., Sahoo, T., Kang, S.H., Cheung, S.W., Lupski, J.R., Stankiewicz, P. (2009) Microdeletions including YWHAE in the Miller-Dieker syndrome region on chromosome 17p13.3 result in facial dysmorphisms, growth restriction, and cognitive impairment. J Med Genet 46, 825–33.PubMedGoogle Scholar
  27. 27.
    Yatsenko, S.A., Brundage, E.K., Roney, E.K., Cheung, S.W., Chinault, A.C., Lupski, J.R. (2009) Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum Mol Genet 18, 1924–36.PubMedGoogle Scholar
  28. 28.
    Vissers, L.E.L.M., Bhatt, S.S., Janssen, I.M., Xia, Z., Lalani, S.R., Pfundt, R., Derwinska, K., de Vries, B.B.A., Gilissen, C., Hoischen, A., Nesteruk, M., Wisniowiecka-Kowalnik, B., Smyk, M., Brunner, H.G., Cheung, S.W., van Kessel, A.D, Veltman, J.A., Stankiewicz, P. (2009) Rare pathogenic microdeletions and tandem duplications are microhomology-mediated and stimulated by local genomic architecture. Hum Molec Genet 18, 3579–93.Google Scholar
  29. 29.
    Shaffer, L.G., and Lupski J.R. (2000) Molecular mechanisms for constitutional chromosomal rearrangements in humans. Annu Rev Genet 34, 297–329.PubMedGoogle Scholar
  30. 30.
    Lupski, J.R. (2007) Genomic rearrangements and sporadic disease. Nat Genet 39, S43–7.PubMedGoogle Scholar
  31. 31.
    Turner, D.J., Miretti, M., Rajan, D., Fiegler, H., Carter, N.P., Blayney, M.L., Beck, S., Hurles, M.E. (2008) Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet 40, 90–5.PubMedGoogle Scholar
  32. 32.
    Kurotaki, N., Harada, N., Shimokawa, O., Miyake, N., Kawame, H., Uetake, K., Makita, Y., Kondoh, T., Ogata, T., Hasegawa, T., Nagai, T., Ozaki, T., Touyama, M., Shenhav, R., Ohashi, H., Medne, L., Shiihara, T., Ohtsu, S., Kato, Z., Okamoto, N., Nishimoto, J., Lev, D., Miyoshi, Y., Ishikiriyama, S., Sonoda, T., Sakazume, S., Fukushima, Y., Kurosawa, K., Cheng, J.F., Yoshiura, K., Ohta, T., Kishino, T., Niikawa, N., Matsumoto, N. (2003) Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion. Hum Mutat 22, 378–87.PubMedGoogle Scholar
  33. 33.
    Koolen, D.A., Sharp, A.J., Hurst, J.A., Firth, H.V., Knight, S.J., Goldenberg, A., Saugier-Veber, P., Pfundt, R., Vissers, L.E., Destree, A., Grisart, B., Rooms, L., Van der, A.N., Field, M., Hackett, A., Bell, K., Nowaczyk, M.J., Mancini, G.M., Poddighe, P.J., Schwartz, C.E., Rossi, E., De, G.M., ntonacci-Fulton, L.L., McLellan, M.D., Garrett, J.M., Wiechert, M.A., Miner, T.L., Crosby, S., Ciccone, R., Willatt, L., Rauch, A., Zenker, M., Aradhya, S., Manning, M.A., Strom, T.M., Wagenstaller, J., Krepischi-Santos, A.C., Vianna-Morgante, A.M., Rosenberg, C., Price, S.M., Stewart, H., Shaw-Smith, C., Brunner, H.G., Wilkie, A.O., Veltman, J.A., Zuffardi, O., Eichler, E.E., de Vries, B.B. (2008) Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet 45, 710–20.Google Scholar
  34. 34.
    Stefansson, H., Helgason, A., Thorleifsson, G., Steinthorsdottir, V., Masson, G., Barnard, J., Baker, A., Jonasdottir, A., Ingason, A., Gudnadottir, V.G., Desnica, N., Hicks, A., Gylfason, A., Gudbjartsson, D.F., Jonsdottir, G.M., Sainz, J., Agnarsson, K., Birgisdottir, B., Ghosh, S., Olafsdottir, A., Cazier, J.B., Kristjansson, K., Frigge, M.L., Thorgeirsson, T.E., Gulcher, J.R., Kong, A., Stefansson, K. (2005) A common inversion under selection in Europeans. Nat Genet 37, 129–37.PubMedGoogle Scholar
  35. 35.
    Sharp, A.J., Locke, D.P., McGrath, S.D., Cheng, Z., Bailey, J.A., Vallente, R.U., Pertz, L.M., Clark, R.A., Schwartz, S., Segraves, R., Oseroff, V.V., Albertson, D.G., Pinkel, D., Eichler, E.E. (2005) Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77, 78–88.PubMedGoogle Scholar
  36. 36.
    Sharp, A.J., Hansen, S., Selzer, R.R., Cheng, Z., Regan, R., Hurst, J.A., Stewart, H., Price, S.M., Blair, E., Hennekam, R.C., Fitzpatrick, C.A., Segraves, R., Richmond, T.A., Guiver, C., Albertson, D.G., Pinkel, D., Eis, P.S., Schwartz, S., Knight, S.J., Eichler, E.E. (2006) Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 38, 1038–42.PubMedGoogle Scholar
  37. 37.
    Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., van Ommen, G. J. B., Goodman, R. H., Peters, D. J. M., Breuning, M. H. (1995) Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348–51.PubMedGoogle Scholar
  38. 38.
    Matsuura, T., Sutcliffe, J.S., Fang, P., Galjaard, R.-J., Jiang, Y., Benton, C.S., Rommens, J.M., Beaudet, A.L. (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet 15, 74–7.PubMedGoogle Scholar
  39. 39.
    Li, L., Krantz, I.D., Deng, Y., Genin, A., Banta, A.B., Collins, C.C., Qi, M., Trask, B.J., Kuo, W.L., Cochran, J., Costa, T., Pierpont, M.E., Rand, E.B., Piccoli, D.A., Hood, L., Spinner, N.B. (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16, 243–51.PubMedGoogle Scholar
  40. 40.
    Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., Zoghbi, H.Y. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23, 185–8.PubMedGoogle Scholar
  41. 41.
    Kurotaki, N., Imaizumi, K., Harada, N., Masuno, M., Kondoh, T., Nagai, T., Ohashi, H., Naritomi, K., Tsukahara, M., Makita, Y., Sugimoto, T., Sonoda, T., Hasegawa, T., Chinen, Y., Tomita Ha, H.A., Kinoshita, A., Mizuguchi, T., Yoshiura Ki, K., Ohta, T., Kishino, T., Fukushima, Y., Niikawa, N., Matsumoto, N. (2002) Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30, 365–6.PubMedGoogle Scholar
  42. 42.
    Slager, R.E., Newton, T.L., Vlangos, C.N., Finucane, B., Elsea, S.H. (2003) Mutations in RAI1 associated with Smith-Magenis ­syndrome. Nat Genet 33, 466–8.PubMedGoogle Scholar
  43. 43.
    Vissers, L.E.L.M., van Ravenswaaij, C.M., Admiraal, R., Hurst, J.A., de Vries, B.B., Janssen, I.M., van der Vliet, W.A., Huys, E.H., de Jong, P.J., Hamel, B.C., Schoenmakers, E.F., Brunner, H.G., Veltman, J.A., van Kessel, A.G. (2004) Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat Genet 36, 955–7.PubMedGoogle Scholar
  44. 44.
    Krantz, I. D., McCallum, J., DeScipio, C., Kaur, M., Gillis, L. A., Yaeger, D., Jukofsky, L., Wasserman, N., Bottani, A., Morris, C. A., Nowaczyk, M. J. M., Toriello, H., Bamshad, M.J., Carey, J.C., Rappaport, E., Kawauchi, S., Lander, A.D., Calof, A.L., Li, H.H., Devoto, M., Jackson, L.G. (2004) Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet 36, 631–5.PubMedGoogle Scholar
  45. 45.
    Tonkin, E. T., Wang, T.-J., Lisgo, S., Bamshad, M. J., Strachan, T. (2004) NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet 36, 636–41.PubMedGoogle Scholar
  46. 46.
    van Bokhoven, H., Celli, J., van Reeuwijk, J., Rinne, T., Glaudemans, B., van Beusekom, E., Rieu, P., Newbury-Ecob, R.A., Chiang, C., Brunner, H.G. (2005) MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat Genet 37, 465–7.PubMedGoogle Scholar
  47. 47.
    Stankiewicz, P., Sen, P., Bhatt, S.S., Storer, M., Xia, Z., Bejjani, B.A., Ou, Z., Wiszniewska, J., Driscoll, D.J., Maisenbacher, M.K., Bolivar, J., Bauer, M., Zackai, E.H., McDonald-McGinn, D., Nowaczyk, M.M., Murray, M., Hustead, V., Mascotti, K., Schultz, R., Hallam, L., McRae, D., Nicholson, A.G., Newbury, R., Durham-O’Donnell, J., Knight, G., Kini, U., Shaikh, T.H., Martin, V., Tyreman, M., Simonic, I., Willatt, L., Paterson, J., Mehta, S., Rajan, D., Fitzgerald, T., Gribble, S., Prigmore, E., Patel, A., Shaffer, L.G., Carter, N.P., Cheung, S.W., Langston, C, Shaw-Smith, C. (2009) Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 84, 780–91.PubMedGoogle Scholar
  48. 48.
    de Vries, B.B., Pfundt, R., Leisink, M., Koolen, D.A., Vissers, L.E., Janssen, I.M., Reijmersdal, S., Nillesen, W.M., Huys, E.H., Leeuw, N., Smeets, D., Sistermans, E.A., Feuth, T., van Ravenswaaij-Arts, C.M., van Kessel, A.G., Schoenmakers, E.F., Brunner, H.G., Veltman, J.A. (2005) Diagnostic genome profiling in mental retardation. Am J Hum Genet 77, 606–16.Google Scholar
  49. 49.
    Schoumans, J., Ruivenkamp, C., Holmberg, E., Kyllerman, M., Anderlid, B.M., Nordenskjold, M. (2005) Detection of ­chromosomal imbalances in children with ­idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH). J Med Genet 42, 699–705.PubMedGoogle Scholar
  50. 50.
    Autism Genome Project Consortium (AGPC)., Szatmari, P., Paterson, A.D., Zwaigenbaum, L., Roberts, W., Brian, J., Liu, X.Q., Vincent, J.B., Skaug, J.L., Thompson, A.P., Senman, L., Feuk, L., Qian, C., Bryson, S.E., Jones, M.B., Marshall, C.R., Scherer, S.W., Vieland, V.J., Bartlett, C., Mangin, L.V., Goedken, R., Segre, A., Pericak-Vance, M.A., Cuccaro, M.L., Gilbert, J.R., Wright, H.H., Abramson, R.K., Betancur, C., Bourgeron, T., Gillberg, C., Leboyer, M., Buxbaum, J.D., Davis, K.L., Hollander, E., Silverman, J.M., Hallmayer, J., Lotspeich, L., Sutcliffe, J.S., Haines, J.L., Folstein, S.E., Piven, J., Wassink, T.H., Sheffield, V., Geschwind, D.H., Bucan, M., Brown, W.T., Cantor, R.M., Constantino, J.N., Gilliam, T.C., Herbert, M., Lajonchere, C., Ledbetter, D.H., Lese-Martin, C., Miller, J., Nelson, S., Samango-Sprouse, C.A., Spence, S., State, M., Tanzi, R.E., Coon, H., Dawson, G., Devlin, B., Estes, A., Flodman, P., Klei, L., McMahon, W.M., Minshew, N., Munson, J., Korvatska, E., Rodier, P.M., Schellenberg, G.D., Smith, M., Spence, M.A., Stodgell, C., Tepper, P.G., Wijsman, E.M., Yu, C.E., Rogé, B., Mantoulan, C., Wittemeyer, K., Poustka, A., Felder, B., Klauck, S.M., Schuster, C., Poustka, F., Bölte, S., Feineis-Matthews, S., Herbrecht, E., Schmötzer, G., Tsiantis, J., Papanikolaou, K., Maestrini, E., Bacchelli, E., Blasi, F., Carone, S., Toma, C., Van Engeland, H., de Jonge, M., Kemner, C., Koop, F., Langemeijer, M., Hijmans, C., Staal, W.G., Baird, G., Bolton, P.F., Rutter, M.L., Weisblatt, E., Green, J., Aldred, C., Wilkinson, J.A., Pickles, A., Le Couteur, A., Berney, T., McConachie, H., Bailey, A.J., Francis, K., Honeyman, G., Hutchinson, A., Parr, J.R., Wallace, S., Monaco, A.P., Barnby, G., Kobayashi, K., Lamb, J.A., Sousa, I., Sykes, N., Cook, E.H., Guter, S.J., Leventhal, B.L., Salt, J., Lord, C., Corsello, C., Hus, V., Weeks, D.E., Volkmar, F., Tauber, M., Fombonne, E., Shih, A., Meyer, K.J. (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39, 19–28.Google Scholar
  51. 51.
    Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y.H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M.C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, K., Wigler, M. (2007) Strong association of de novo copy-number mutations with autism. Science 316, 445–9.PubMedGoogle Scholar
  52. 52.
    Marshall, C.R., Noor, A., Vincent, J.B., Lionel, A.C., Feuk, L., Skaug, J., Shago, M., Moessner, R., Pinto, D., Ren, Y., Thiruvahindrapduram, B., Fiebig, A., Schreiber, S., Friedman, J., Ketelaars, C.E., Vos, Y.J., Ficicioglu, C., Kirkpatrick, S., Nicolson, R., Sloman, L., Summers, A., Gibbons, C.A., Teebi, A., Chitayat, D., Weksberg, R., Thompson, A., Vardy, C., Crosbie, V., Luscombe, S., Baatjes, R., Zwaigenbaum, L., Roberts, W., Fernandez, B., Szatmari, P., Scherer, S.W. (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82, 477–88.PubMedGoogle Scholar
  53. 53.
    International Schizophrenia Consortium. (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–41.Google Scholar
  54. 54.
    Lu, X.Y., Phung, M.T., Shaw, C.A., Pham, K., Neil, S.E., Patel, A., Sahoo, T., Bacino, C.A., Stankiewicz, P., Kang, S.H., Lalani, S., Chinault, A.C., Lupski, J.R., Cheung, S.W., Beaudet, A.L. (2008) Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics 122, 1310–8.PubMedGoogle Scholar
  55. 55.
    McMullan, D.J., Bonin, M., Hehir-Kwa, J.Y., de Vries, B.B., Dufke, A., Rattenberry, E., Steehouwer, M., Moruz, L., Pfundt, R., de, L.N., Riess, A., tug-Teber, O., Enders, H., Singer, S., Grasshoff, U., Walter, M., Walker, J.M., Lamb, C.V., Davison, E.V., Brueton, L., Riess, O., Veltman, J.A. (2009) Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: A multicenter study. Hum Mutat 30, 1082–92.Google Scholar
  56. 56.
    Bochukova, E.G., Huang, N., Keogh, J., Henning, E., Purmann, C., Blaszczyk, K., Saeed, S., Hamilton-Shield, J., Clayton-Smith, J., O’Rahilly, S., Hurles, M.E., Farooqi, I.S. (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature, 463, 666–70Google Scholar
  57. 57.
    de Kovel, C.G., Trucks, H., Helbig, I., Mefford, H.C., Baker, C., Leu, C., Kluck, C., Muhle, H., von Spiczak, S., Ostertag, P., Obermeier, T., Kleefuss-Lie, A.A., Hallmann, K., Steffens, M., Gaus, V., Klein, K.M., Hamer, H.M., Rosenow, F., Brilstra, E.H., Trenité, D.K., Swinkels, M.E., Weber, Y.G., Unterberger, I., Zimprich, F., Urak, L., Feucht, M., Fuchs, K., Møller, R.S., Hjalgrim, H., De Jonghe, P., Suls, A., Rückert, I.M., Wichmann, H.E., Franke, A., Schreiber, S., Nürnberg, P., Elger, C.E., Lerche, H., Stephani, U., Koeleman, B.P., Lindhout, D., Eichler, E.E., Sander, T. (2010) Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133, 23–32.PubMedGoogle Scholar
  58. 58.
    Brunetti-Pierri, N., Berg, J.S., Scaglia, F., Belmont, J., Bacino, C.A., Sahoo, T., Lalani, S.R., Graham, B., Lee, B., Shinawi, M., Shen, J., Kang, S.H., Pursley, A., Lotze, T., Kennedy, G., Lansky-Shafer, S., Weaver, C., Roeder, E.R., Grebe, T.A., Arnold, G.L., Hutchison, T., Reimschisel, T., Amato, S., Geragthy, M.T., Innis, J.W., Obersztyn, E., Nowakowska, B., Rosengren, S.S., Bader, P.I., Grange, D.K., Naqvi, S., Garnica, A.D., Bernes, S.M., Fong, C.T., Summers, A., Walters, W.D., Lupski, J.R., Stankiewicz, P., Cheung, S.W., Patel, A. (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40, 1466–71.PubMedGoogle Scholar
  59. 59.
    Mefford, H.C., Sharp, A.J., Baker, C., Itsara, A., Jiang, Z., Buysse, K., Huang, S., Maloney, V.K., Crolla, J.A., Baralle, D., Collins, A., Mercer, C., Norga, K., de Ravel, T., Devriendt, K., Bongers, E.M., de Leeuw, N., Reardon, W., Gimelli, S., Bena, F., Hennekam, R.C., Male, A., Gaunt, L., Clayton-Smith, J., Simonic, I., Park, S.M., Mehta, S.G., Nik-Zainal, S., Woods, C.G., Firth, H.V., Parkin, G., Fichera, M., Reitano, S., Lo Giudice, M., Li, K.E., Casuga, I., Broomer, A., Conrad, B., Schwerzmann, M., Räber, L., Gallati, S., Striano, P., Coppola, A., Tolmie, J.L., Tobias, E.S., Lilley, C., Armengol, L., Spysschaert, Y., Verloo, P., De Coene, A., Goossens, L., Mortier, G., Speleman, F., van Binsbergen, E., Nelen, M.R., Hochstenbach, R., Poot, M., Gallagher, L., Gill, M., McClellan, J., King, M.C., Regan, R., Skinner, C., Stevenson, R.E., Antonarakis, S.E., Chen, C., Estivill, X., Menten, B., Gimelli, G., Gribble, S., Schwartz, S., Sutcliffe, J.S., Walsh, T., Knight, S.J., Sebat, J., Romano, C., Schwartz, C.E., Veltman, J.A., de Vries, B.B., Vermeesch, J.R., Barber, J.C., Willatt, L., Tassabehji, M., Eichler, E.E. (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359, 1685–99.PubMedGoogle Scholar
  60. 60.
    Stefansson, H., Rujescu, D., Cichon, S., Pietiläinen, O.P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A., Halldorsson, B.V., Gudbjartsson, D., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Möller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di Forti, M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Mühleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L.A., Franke, B., GROUP., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B., Nöthen, M.M., Peltonen, L., Collier, D.A., St Clair, D., Stefansson, K. (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455, 232– 6.Google Scholar
  61. 61.
    Sharp, A.J., Mefford, H.C., Li, K., Baker, C., Skinner, C., Stevenson, R.E., Schroer, R.J., Novara, F., De Gregori, M., Ciccone, R., Broomer, A., Casuga, I., Wang, Y., Xiao, C., Barbacioru, C., Gimelli, G., Bernardina, B.D., Torniero, C., Giorda, R., Regan, R., Murday, V., Mansour, S., Fichera, M., Castiglia, L., Failla, P., Ventura, M., Jiang, Z., Cooper, G.M., Knight, S.J., Romano, C., Zuffardi, O., Chen, C., Schwartz, C.E., Eichler, E.E. (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40, 322–8.PubMedGoogle Scholar
  62. 62.
    Ben-Shachar, S., Lanpher, B., German, J.R., Qasaymeh, M., Potocki, L., Nagamani, S.C., Franco, L.M., Malphrus, A., Bottenfield, G.W,, Spence, J.E., Amato, S., Rousseau, J.A., Moghaddam, B., Skinner, C., Skinner, S.A., Bernes, S., Armstrong, N., Shinawi, M., Stankiewicz, P., Patel, A., Cheung, S.W., Lupski, J.R., Beaudet, A.L., Sahoo, T. (2009) Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J Med Genet 46, 382–8.PubMedGoogle Scholar
  63. 63.
    van Bon, B.W., Mefford, H.C., Menten, B., Koolen, D.A., Sharp, A.J., Nillesen, W.M., Innis, J.W., de Ravel, T.J., Mercer, C.L., Fichera, M., Stewart, H., Connell, L.E., Ounap, K., Lachlan, K., Castle, B., Van der Aa, N., van Ravenswaaij, C., Nobrega, M.A., Serra-Juhé, C., Simonic, I., de Leeuw, N., Pfundt, R., Bongers, E.M., Baker, C., Finnemore, P., Huang, S., Maloney, V.K., Crolla, J.A., van Kalmthout, M., Elia, M., Vandeweyer, G., Fryns, J.P., Janssens, S., Foulds, N., Reitano, S., Smith, K., Parkel, S., Loeys, B., Woods, C.G., Oostra, A., Speleman, F., Pereira, A.C., Kurg, A., Willatt, L., Knight, S.J., Vermeesch, J.R., Romano, C., Barber, J.C., Mortier, G., Pérez-Jurado, L.A., Kooy, F., Brunner, H.G., Eichler, E.E., Kleefstra, T., de Vries, B.B. (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 46, 511–23.Google Scholar
  64. 64.
    Miller, D.T., Shen, Y., Weiss, L.A., Korn, J., Anselm, I., Bridgemohan, C., Cox, G.F., Dickinson, H., Gentile, J., Harris, D.J., Hegde, V., Hundley, R., Khwaja, O., Kothare, S., Luedke, C., Nasir, R., Poduri, A., Prasad, K., Raffalli, P., Reinhard, A., Smith, S.E., Sobeih, M.M., Soul, J.S., Stoler, J., Takeoka, M., Tan, W.H., Thakuria, J., Wolff, R., Yusupov, R., Gusella, J.F., Daly, M.J., Wu, B.L. (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 46, 242–8.PubMedGoogle Scholar
  65. 65.
    Kumar, R.A., KaraMohamed, S., Sudi, J., Conrad, D.F., Brune, C., Badner, J.A., Gilliam, T.C., Nowak, N.J., Cook, E.H. Jr., Dobyns, W.B., Christian, S.L. (2008) Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 17, 628–38.PubMedGoogle Scholar
  66. 66.
    Weiss, L.A., Shen, Y., Korn, J.M., Arking, D.E., Miller, D.T., Fossdal, R., Saemundsen, E., Stefansson, H., Ferreira, M.A., Green, T., Platt, O.S., Ruderfer, D.M., Walsh, C.A., Altshuler, D., Chakravarti, A., Tanzi, R.E., Stefansson, K., Santangelo, S.L., Gusella, J.F., Sklar, P., Wu, B.L., Daly, M.J. (2008) Autism Consortium. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358, 667–75.PubMedGoogle Scholar
  67. 67.
    McCarthy, S.E., Makarov, V., Kirov, G., Addington, A.M., McClellan, J., Yoon, S., Perkins, D.O., Dickel, D.E., Kusenda, M., Krastoshevsky, O., Krause, V., Kumar, R.A., Grozeva, D., Malhotra, D., Walsh, T., Zackai, E.H., Kaplan, P., Ganesh, J., Krantz, I.D., Spinner, N.B., Roccanova, P., Bhandari, A., Pavon, K., Lakshmi, B., Leotta, A., Kendall, J., Lee, Y.H., Vacic, V., Gary, S., Iakoucheva, L.M., Crow, T.J., Christian, S.L., Lieberman, J.A., Stroup, T.S., Lehtimäki, T., Puura, K., Haldeman-Englert, C., Pearl, J., Goodell, M., Willour, V.L., Derosse, P., Steele, J., Kassem, L., Wolff, J., Chitkara, N., McMahon, F.J., Malhotra, A.K., Potash, J.B., Schulze, T.G., Nöthen, M.M., Cichon, S., Rietschel, M., Leibenluft, E., Kustanovich, V., Lajonchere, C.M., Sutcliffe, J.S., Skuse, D., Gill, M., Gallagher, L., Mendell, N.R., Wellcome Trust Case Control Consortium., Craddock, N., Owen, M.J., O’Donovan, M.C., Shaikh, T.H., Susser, E., Delisi, L.E., Sullivan, P.F., Deutsch, C.K., Rapoport, J., Levy, D.L., King, M.C., Sebat, J. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41, 1223–7.PubMedGoogle Scholar
  68. 68.
    Shinawi, M., Liu, P., Kang, S.H., Shen, J., Belmont, J.W., Scott, D.A., Probst, F.J., Craigen, W.J., Graham, B., Pursley, A., Clark, G., Lee, J., Proud, M., Stocco, A., Rodriguez, D., Kozel, B., Sparagana, S., Roeder, E., McGrew, S., Kurczynski, T., Allison, L., Amato, S., Savage, S., Patel, A., Stankiewicz, P., Beaudet, A., Cheung, S.W., Lupski, J.R. (2010) Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioral problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 47, 332–41.Google Scholar
  69. 69.
    Crespi, B., Summers, K., Dorus, S. (2009) Genomic sister-disorders of neurodevelopment: an evolutionary approach. Evolutionary Applications 2, 81–100.Google Scholar
  70. 70.
    Crespi, B., Stead, P., Elliot, M. (2010) Evolution in health and medicine sackler colloquium: comparative genomics of autism and schizophrenia. Proc Natl Acad Sci USA 107, Suppl: 1736–41.Google Scholar
  71. 71.
    Rovelet-Lecrux, A., Hannequin, D., Raux, G., Le Meur, N., Laquerrière, A., Vital, A., Dumanchin, C., Feuillette, S., Brice, A., Vercelletto, M., Dubas, F., Frebourg, T., Campion, D. (2006) APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38, 24–6.PubMedGoogle Scholar
  72. 72.
    Singleton, A.B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., Lincoln, S., Crawley, A., Hanson, M., Maraganore, D., Adler, C., Cookson, M.R., Muenter, M., Baptista, M., Miller, D., Blancato, J., Hardy, J., Gwinn-Hardy, K. (2003) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302, 841.PubMedGoogle Scholar
  73. 73.
    Chartier-Harlin, M.C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., Waucquier, N., Defebvre, L., Amouyel, P., Farrer, M., Destée, A. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364, 1167– 9.PubMedGoogle Scholar
  74. 74.
    Ibáñez, P., Bonnet, A.M., Debarges, B., Lohmann, E., Tison, F., Pollak, P., Agid, Y., Dürr, A., Brice, A. (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364, 1169–71.PubMedGoogle Scholar
  75. 75.
    Le Maréchal, C., Masson, E., Chen, J.M., Morel, F., Ruszniewski, P., Levy, P., Férec, C. (2006) Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nat Genet 38, 1372–4.PubMedGoogle Scholar
  76. 76.
    Fellermann, K., Stange, D.E., Schaeffeler, E., Schmalzl, H., Wehkamp, J., Bevins, C.L., Reinisch, W., Teml, A., Schwab, M., Lichter, P., Radlwimmer, B., Stange, E.F. (2006) A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy-number predisposes to Crohn disease of the colon. Am J Hum Genet 79, 439–48.PubMedGoogle Scholar
  77. 77.
    McCarroll, S.A., Huett, A., Kuballa, P., Chilewski, S.D., Landry, A., Goyette, P., Zody, M.C., Hall, J.L., Brant, S.R., Cho, J.H., Duerr, R.H., Silverberg, M.S., Taylor, K.D., Rioux, J.D., Altshuler, D., Daly, M.J., Xavier, R.J. (2008) Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet 40, 1107–12.PubMedGoogle Scholar
  78. 78.
    Aitman, T.J., Dong, R., Vyse, T.J., Norsworthy, P.J., Johnson, M.D., Smith, J., Mangion, J., Roberton-Lowe, C., Marshall, A.J., Petretto, E., Hodges, M.D., Bhangal, G., Patel, S.G., Sheehan-Rooney, K., Duda, M., Cook, P.R., Evans, D.J., Domin, J., Flint, J., Boyle, J.J., Pusey, C.D., Cook, H.T. (2006) Copy-number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature 439, 851–5.PubMedGoogle Scholar
  79. 79.
    Hollox, E.J., Huffmeier, U., Zeeuwen, P.L., Palla, R., Lascorz, J., Rodijk-Olthuis, D., van de Kerkhof, P.C., Traupe, H., de Jongh, G., den Heijer, M., Reis, A., Armour, J.A., Schalkwijk, J. (2008) Psoriasis is associated with increased beta-defensin genomic copy-number. Nat Genet 40, 23–5.PubMedGoogle Scholar
  80. 80.
    Willcocks, L.C., Lyons, P.A., Clatworthy, M.R., Robinson, J.I., Yang, W., Newland, S.A., Plagnol, V., McGovern, N.N., Condliffe, A.M., Chilvers, E.R., Adu, D., Jolly, E.C., Watts, R., Lau, Y.L., Morgan, A.W., Nash, G., Smith, K.G. (2008) Copy-number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake. J Exp Med 205, 1573–82.PubMedGoogle Scholar
  81. 81.
    Lupski, J.R., Chance, P.F., Garcia, C.A. (1993) Inherited primary peripheral neuropathies. Molecular genetics and clinical implications of CMT1A and HNPP. JAMA 270, 2326–30.PubMedGoogle Scholar
  82. 82.
    Lupski, J.R., Stankiewicz, P. (2005) Genomic disorder mechanisms elucidated by breakpoint analysis of 17p rearrangements. PLoS Genet 1, e49.PubMedGoogle Scholar
  83. 83.
    Rujescu, D., Ingason, A., Cichon, S., Pietiläinen, O.P., Barnes, M.R., Toulopoulou, T., Picchioni, M., Vassos, E., Ettinger, U., Bramon, E., Murray, R., Ruggeri, M., Tosato, S., Bonetto, C., Steinberg, S., Sigurdsson, E., Sigmundsson, T., Petursson, H., Gylfason, A., Olason, P.I., Hardarsson, G., Jonsdottir, G.A., Gustafsson, O., Fossdal, R., Giegling, I., Möller, H.J., Hartmann, A.M., Hoffmann, P., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Djurovic, S., Melle, I., Andreassen, O.A., Hansen, T., Werge, T., Kiemeney, L.A., Franke, B., Veltman, J., Buizer-Voskamp, J.E., GROUP Investigators., Sabatti, C., Ophoff, R.A., Rietschel, M., Nöthen, M.M., Stefansson, K., Peltonen, L., St Clair, D., Stefansson, H., Collier, D.A. (2009) Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet 18, 988–96.Google Scholar
  84. 84.
    Lifton, R.P., Dluhy, R.G., Powers, M., Rich, G.M., Cook, S., Ulick, S., Lalouel, J.-M. (1992) A chimaeric 11-beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355, 262–5.PubMedGoogle Scholar
  85. 85.
    Lettice, L.A., Horikoshi, T., Heaney, S.J.H., van Baren, M.J., van der Linde, H.C., Breedveld, G.J., Joosse, M., Akarsu, N., Oostra, B.A., Endo, N., Shibata, M., Suzuki, M., Takahashi, E., Shinka, T., Nakahori, Y., Ayusawa, D., Nakabayashi, K., Scherer, S.W., Heutink, P., Hill, R.E., Noji, S. (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci USA 99, 7548–53.PubMedGoogle Scholar
  86. 86.
    Velagaleti, G.V., Bien-Willner, G.A., Northup, J.K., Lockhart, L.H., Hawkins, J.C., Jalal, S.M., Withers, M., Lupski, J.R., Stankiewicz, P. (2005) Position effects due to chromosome breakpoints that map approximately 900 Kb upstream and approximately 1.3 Mb downstream of SOX9 in two patients with campomelic dysplasia. Am J Hum Genet 76, 652–62.PubMedGoogle Scholar
  87. 87.
    Pop, R., Conz, C., Lindenberg, K.S., Blesson, S., Schmalenberger, B., Briault, S., Pfeifer, D., Scherer, G. (2004) Screening of the 1 Mb SOX9 5’ control region by arrayCGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal. J Med Genet 41, e47.PubMedGoogle Scholar
  88. 88.
    Beysen, D., Raes, J., Leroy, B.P., Lucassen, A., Yates, J.R., Clayton-Smith, J., Ilyina, H., Brooks, S.S., Christin-Maitre, S., Fellous, M., Fryns, J.P., Kim, J.R., Lapunzina, P., Lemyre, E., Meire, F., Messiaen, L.M., Oley, C., Splitt, M., Thomson, J., Van de Peer, Y., Veitia, R.A., De Paepe, A., De Baere, E. (2005) Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome. Am J Hum Genet 77, 205–18.PubMedGoogle Scholar
  89. 89.
    Kleinjan, D.A., van Heyningen, V. (2005) Long-Range Control of Gene Expression. Emerging Mechanisms and Disruption in Disease. Am J Hum Genet 76, 8–32.Google Scholar
  90. 90.
    Klopocki, E., Ott, C. E., Benatar, N., Ullmann, R., Mundlos, S., Lehmann, L. (2008) A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome. J Med Genet 45, 370–5.PubMedGoogle Scholar
  91. 91.
    Dathe, K., Kjaer, K.W., Brehm, A., Meinecke, P., Nürnberg, P., Neto, J.C., Brunoni, D., Tommerup, N., Ott, C.E., Klopocki, E., Seemann, P., Mundlos, S. (2009) Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Am J Hum Genet 84, 483–92.PubMedGoogle Scholar
  92. 92.
    Kurth, I., Klopocki, E., Stricker, S., van Oosterwijk, J., Vanek, S., Altmann, J., Santos, H.G., van Harssel, J.J., de Ravel, T., Wilkie, A.O., Gal, A., Mundlos, S. (2009) Duplications of noncoding elements 5’ of SOX9 are associated with brachydactyly-anonychia. Nat Genet 41, 862–3.PubMedGoogle Scholar
  93. 93.
    Kurotaki, N,, Shen, J.J., Touyama, M., Kondoh, T., Visser, R., Ozaki, T., Nishimoto, J., Shiihara, T., Uetake, K., Makita, Y., Harada, N., Raskin, S., Brown, C.W., Höglund, P., Okamoto, N., Lupski, J.R. (2005) Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency. Genet Med 7, 479–83.PubMedGoogle Scholar
  94. 94.
    Trask, B., Pinkel, D., Van den Engh, G.J. (1989) The proximity of DNA sequences in interphase cell nuclei is correlated to genomic distance and permits ordering of cosmids spanning 250 kilobase pairs. Genomics 5, 710–7.PubMedGoogle Scholar
  95. 95.
    Van den Engh, G., Van den Sachs, R., Trask, B.J. (1992) Estimating genomic distance from DNA sequence location in cell nuclei by a random walk model. Science 257, 1410–2.PubMedGoogle Scholar
  96. 96.
    Dermitzakis, E.T., Reymond, A., Scamuffa, N., Ucla, C., Kirkness, E., Rossier, C., Antonarakis, S.E. (2003) Evolutionary ­discrimination of mammalian conserved non-genic sequences (CNGs). Science 302, 1033–5.PubMedGoogle Scholar
  97. 97.
    Dermitzakis, E.T., Reymond, A., Antonarakis, S.E. (2005) Conserved non-genic sequences - an unexpected feature of mammalian genomes. Nat Rev Genet 6, 151–7.PubMedGoogle Scholar
  98. 98.
    Tanabe, H. Muller, S., Neusser, M., von Hase, J., Calcagno, E., Cremer, M., Solovei, I., Cremer, C., Cremer, T. (2002) Evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates. Proc Natl Acad Sci USA 99: 4424–9.PubMedGoogle Scholar
  99. 99.
    Glazko, G.V., Koonin, E.V., Rogozin, I.B., Shabalina, S.A. (2003). A significant fraction of conserved noncoding DNA in human and mouse consists of predicted matrix attachment regions. Trends Genet 19, 119–24.PubMedGoogle Scholar
  100. 100.
    Kioussis, D., Vanin, E., deLange, T., Flavell, R.A., Grosveld, F.G. (1983) β-globin gene inactivation by DNA traslocation un γ-β-thalassaemia. Nature 306, 662–6.PubMedGoogle Scholar
  101. 101.
    Driscoll, M.C., Dobkin, C.S., Alter, B.P. (1989). γ-δ-β-Thalassaemia due to a de novo mutation deleting the 5’ β-globin gene activation-region hypersensitive sites. Proc Natl Acad Sci USA 86, 7470–4.PubMedGoogle Scholar
  102. 102.
    de Kok, YJ., van der Maarel, S.M., Bitner-Glindzicz, M., Huber, I., Monaco, A.P., Malcolm, S., Pembrey, M.E., Ropers, H.H., Cremers, F.P. (1995). Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science 267, 685–8.PubMedGoogle Scholar
  103. 103.
    de Kok, Y.J., Vossenaar, E.R., Cremers, C.W., Dahl, N., Laporte, J., Hu, L.J., Lacombe, D., Fischel-Ghodsian, N., Friedman, R.A., Parnes, L.S., Thorpe, P., Bitner-Glindzicz, M., Pander, H.J., Heilbronner, H., Graveline, J., den Dunnen, J.T., Brunner, H.G., Ropers, H.H., Cremers, F.P. (1996). Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum Mol Genet 5, 1229–35.PubMedGoogle Scholar
  104. 104.
    Lettice, L.A., Heaney, S.J., Purdie, L.A., Li, L., de Beer, P., Oostra, B.A., Goode, D., Elgar, G., Hill, R.E., de Graaff, E. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12, 1725–35.PubMedGoogle Scholar
  105. 105.
    Garzon, R., Calin, G.A., Croce, C.M. (2009) MicroRNAs in Cancer. Annu Rev Med 60, 167–79.PubMedGoogle Scholar
  106. 106.
    Mardis, E.R. (2008) Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet 9, 387–402.PubMedGoogle Scholar
  107. 107.
    Levy, S., Sutton, G., Ng, P.C., Feuk, L., Halpern, A.L., Walenz, B.P., Axelrod, N., Huang, J., Kirkness, E.F., Denisov, G., Lin, Y., MacDonald, J.R., Pang, A.W., Shago, M., Stockwell, T.B., Tsiamouri, A., Bafna, V., Bansal, V., Kravitz, S.A., Busam, D.A., Beeson, K.Y., McIntosh, T.C., Remington, K.A., Abril, J.F., Gill, J., Borman, J., Rogers, Y.H., Frazier, M.E., Scherer, S.W., Strausberg, R.L., Venter, J.C. (2007) The diploid genome sequence of an individual human. PLoS Biol 5, e254.PubMedGoogle Scholar
  108. 108.
    Wheeler, D.A., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., He, W., Chen, Y.J., Makhijani, V., Roth, G.T., Gomes, X., Tartaro, K., Niazi, F., Turcotte, C.L., Irzyk, G.P., Lupski, J.R., Chinault, C., Song, X.Z., Liu, Y., Yuan, Y., Nazareth, L., Qin, X., Muzny, D.M., Margulies, M., Weinstock, G.M., Gibbs. R.A., Rothberg, J.M. (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–6.PubMedGoogle Scholar
  109. 109.
    Tarpey, P.S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O’Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., Greenman, C., Xue, Y., Tyler-Smith, C., Thompson, D., Gray, K., Andrews, J., Barthorpe, S., Buck, G., Cole, J., Dunmore, R., Jones, D., Maddison, M., Mironenko, T., Turner, R., Turrell, K., Varian, J., West, S., Widaa, S., Wray, P., Teague, J., Butler, A., Jenkinson, A., Jia, M., Richardson, D., Shepherd, R., Wooster, R., Tejada, M.I., Martinez, F., Carvill, G., Goliath, R., de Brouwer, A.P., van Bokhoven, H., Van Esch, H., Chelly, J., Raynaud, M., Ropers, H.H., Abidi, F.E., Srivastava, A.K., Cox, J., Luo, Y., Mallya, U., Moon, J., Parnau, J., Mohammed, S., Tolmie, J.L., Shoubridge, C., Corbett, M., Gardner, A., Haan, E., Rujirabanjerd, S., Shaw, M., Vandeleur, L., Fullston, T., Easton, D.F., Boyle, J., Partington, M., Hackett, A., Field, M., Skinner, C., Stevenson, R.E., Bobrow, M., Turner, G., Schwartz, C.E., Gecz, J., Raymond, F.L., Futreal, P.A., Stratton, M.R. (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet 41, 535–43.PubMedGoogle Scholar
  110. 110.
    Ng, S.B., Turner, E.H., Robertson, P.D., Flygare, S.D., Bigham, A.W., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E.E., Bamshad, M., Nickerson, D.A., Shendure, J. (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–6.PubMedGoogle Scholar
  111. 111.
    Lupski, J.R., Reid, J.G., Gonzaga-Jauregui, C., Deiros, D.R., Chen, D.C.Y., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D.A., McGuire, A.L., Zhang, F., Stankiewicz, P., Halperin, J.J., Yang, C., Gehman, C., Guo, D., Irikat, R.K., Tom, W., Fantin, N.J., Muzny, D.M., Gibbs, R.A. (2010) Whole-genome sequencing in a patient with Charcot-Marie Tooth neuropathy. N Engl J Med 362, 1181–91.Google Scholar
  112. 112.
    Korbel, J.O., Urban, A.E., Affourtit, J.P., Godwin, B., Grubert, F., Simons, J.F., Kim, P.M., Palejev, D., Carriero, N.J., Du, L., Taillon, B.E., Chen, Z., Tanzer, A., Saunders, A.C., Chi, J., Yang, F., Carter, N.P., Hurles, M.E., Weissman, S.M., Harkins, T.T., Gerstein, M.B., Egholm, M., Snyder, M. (2007) Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420–6.PubMedGoogle Scholar
  113. 113.
    Kidd, J.M., Cooper, G.M., Donahue, W.F., Hayden, H.S., Sampas, N., Graves, T., Hansen, N., Teague, B., Alkan, C., Antonacci, F., Haugen, E., Zerr, T., Yamada, N.A., Tsang, P., Newman, T.L., Tüzün, E., Cheng, Z., Ebling, H.M., Tusneem, N., David, R., Gillett, W., Phelps, K.A., Weaver, M., Saranga, D., Brand, A., Tao, W., Gustafson, E., McKernan, K., Chen, L., Malig, M., Smith, J.D., Korn, J.M., McCarroll, S.A., Altshuler, D.A., Peiffer, D.A., Dorschner, M., Stamatoyannopoulos, J., Schwartz, D., Nickerson, D.A., Mullikin, J.C., Wilson, R.K., Bruhn, L., Olson, M.V., Kaul, R., Smith, D.R., Eichler, E.E. (2008) Mapping and sequencing of structural variation from eight human genomes. Nature 453, 56–64.PubMedGoogle Scholar
  114. 114.
    Li, R., Li, Y., Zheng, H., Luo, R., Zhu, H., Li, Q., Qian, W., Ren, Y., Tian, G., Li, J., Zhou, G., Zhu, X., Wu, H., Qin, J., Jin, X., Li, D., Cao, H., Hu, X., Blanche, H., Cann, H., Zhang, X., Li, S., Bolund, L., Kristiansen, K., Yang, H., Wang, J., Wang, J. (2010) Building the sequence map of the human pan-genome. Nat Biotechnol 28, 57–63.PubMedGoogle Scholar
  115. 115.
    Lupski, J.R. (2007) Structural variation in the human genome. N Engl J Med 356, 1169–7.PubMedGoogle Scholar
  116. 116.
    Hurles, M.E., Willey, D., Matthews, L., Hussain, S.S. (2004) Origins of chromosomal rearrangement hotspots in the human genome: evidence from the AZFa deletion hotspots. Genome Biol 5, R55.PubMedGoogle Scholar
  117. 117.
    Lupski, J.R., Montes de Oca-Luna, R., Slaugenhaupt, S., Pentao, L., Guzzetta, V., Trask, B. J., Saucedo-Cardenas, O., Barker, D. F., Killian, J. M., Garcia, C. A., Chakravarti, A., Patel, P. I. (1991) DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–32.PubMedGoogle Scholar
  118. 118.
    Chance, P.F., Alderson, M.K., Leppig, K.A., Lensch, M.W., Matsunami, N., Smith, B., Swanson, P.D., Odelberg, S.J., Disteche, C.M., Bird, T.D. (1993) DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell 72, 143–51.PubMedGoogle Scholar
  119. 119.
    McDermid, H.E., Morrow, B.E. (2002) Genomic disorders on 22q11. Am J Hum Genet 70, 1077–88.PubMedGoogle Scholar
  120. 120.
    Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R. (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362, 1366–73.PubMedGoogle Scholar
  121. 121.
    Ensenauer, R.E., Adeyinka, A., Flynn, H.C., Michels, V.V., Lindor, N.M., Dawson, D.B., Thorland, E.C., Lorentz, C.P., Goldstein, J.L., McDonald, M.T., Smith, W.E., Simon-Fayard, E., Alexander, A.A., Kulharya, A.S., Ketterling, R.P., Clark, R.D., Jalal, S.M. (2003) Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet 73, 1027–40.PubMedGoogle Scholar
  122. 122.
    Riva, P., Corrado, L., Natacci, F., Castorina, P., Wu, B.-L., Schneider, G. H., Clementi, M., Tenconi, R., Korf, B. R., Larizza, L. (2000) NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am J Hum Genet 66, 100–9.PubMedGoogle Scholar
  123. 123.
    Chai, J.H., Locke, D.P., Greally, J.M., Knoll, J.H., Ohta, T., Dunai, J., Yavor, A., Eichler, E.E. (2003) Nicholls RD Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet 73, 898–925.PubMedGoogle Scholar
  124. 124.
    Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL. (2008) Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nat Genet 40, 719–21.PubMedGoogle Scholar
  125. 125.
    Potocki, L., Shaw, C.J., Stankiewicz, P., Lupski, J.R. (2003) Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis syndrome (del(17)(p11.2p11.2)). Genet Med 5, 430–4.PubMedGoogle Scholar
  126. 126.
    Potocki, L., Bi, W., Treadwell-Deering, D., Carvalho, C.M., Eifert, A., Friedman, E.M., Glaze, D., Krull, K., Lee, J.A., Lewis, R.A., Mendoza-Londono, R., Robbins-Furman, P., Shaw, C., Shi, X., Weissenberger, G., Withers, M., Yatsenko, S.A., Zackai, E.H., Stankiewicz, P., Lupski, J.R. (2007) Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 80, 633–49.PubMedGoogle Scholar
  127. 127.
    Franco, L.M., de Ravel, T., Graham, B.H., Frenkel, S.M., Van Driessche, J., Stankiewicz, P., Lupski, J.R., Vermeesch, J.R., Cheung, S.W. (2010) A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion. Eur J Hum Genet 18, 258–61.PubMedGoogle Scholar
  128. 128.
    Hernández-Martín, A., González-Sarmiento, R., De Unamuno, P. (1999) X-linked ichthyosis: an update. Br J Dermatol 141, 617–27.PubMedGoogle Scholar
  129. 129.
    Tassabehji, M. (2003) Williams-Beuren syndrome: a challenge for genotype-phenotype correlations. Hum Mol Genet 2, R229–37.Google Scholar
  130. 130.
    Somerville, M.J., Mervis, C.B., Young, E.J., Seo, E.J., del Campo, M., Bamforth, S., Peregrine, E., Loo, W., Lilley, M., Pérez-Jurado, L.A., Morris, C.A., Scherer, S.W., Osborne, L.R. (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353, 1694–701.PubMedGoogle Scholar
  131. 131.
    Klopocki, E., Schulze, H., Strauss, G., Ott, C.E., Hall, J., Trotier, F., Fleischhauer, S., Greenhalgh, L., Newbury-Ecob, R.A., Neumann, L.M., Habenicht, R., König, R., Seemanova, E., Megarbane, A., Ropers, H.H., Ullmann, R., Horn, D., Mundlos, S. (2007) Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 80, 232–40.PubMedGoogle Scholar
  132. 132.
    Willatt, L., Cox, J., Barber, J., Cabanas, E.D., Collins, A., Donnai, D., Fitzpatrick, D.R., Maher, E., Martin, H., Parnau, J., Pindar, L., Ramsay, J., Shaw-Smith, C., Sistermans, E.A., Tettenborn, M., Trump, D., de Vries, B.B., Walker, K., Raymond, F.L. (2005) 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome. Am J Hum Genet 77, 154–60.PubMedGoogle Scholar
  133. 133.
    Ballif, B.C., Theisen, A., Coppinger, J., Gowans, G.C., Hersh, J.H., Madan-Khetarpal, S., Schmidt, K.R., Tervo, R., Escobar, L.F., Friedrich, C.A., McDonald, M., Campbell, L., Ming, J.E., Zackai, E.H., Bejjani, B.A., Shaffer, L.G. (2008) Expanding the clinical phenotype of the 3q29 microdeletion syndrome and characterization of the reciprocal microduplication. Mol Cytogenet 1, 8.PubMedGoogle Scholar
  134. 134.
    Devriendt, K., Matthijs, G., Van Dael, R., Gewillig, M., Eyskens, B., Hjalgrim, H., Dolmer, B., McGaughran, J., Bröndum-Nielsen, K., Marynen, P., Fryns, J.P., Vermeesch, J.R. (1999) Delineation of the critical deletion region for congenital heart defects, on chromosome 8p23.1. Am J Hum Genet 64, 1119–26.PubMedGoogle Scholar
  135. 135.
    Barber, J.C., Maloney, V.K., Huang, S., Bunyan, D.J., Cresswell, L., Kinning, E., Benson, A., Cheetham, T., Wyllie, J., Lynch, S.A., Zwolinski, S., Prescott, L., Crow, Y., Morgan, R., Hobson, E. (2008) 8p23.1 duplication syndrome: A novel genomic condition with unexpected complexity revealed by array CGH. Eur J Hum Genet 16, 18–27.PubMedGoogle Scholar
  136. 136.
    Balciuniene, J., Feng, N., Iyadurai, K., Hirsch, B., Charnas, L., Bill, B.R., Easterday, M.C., Staaf, J., Oseth, L., Czapansky-Beilman, D., Avramopoulos, D., Thomas, G.H., Borg, A., Valle, D., Schimmenti, L.A., Selleck, S.B. (2007) Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 80, 938–47.PubMedGoogle Scholar
  137. 137.
    Cook, E.H. Jr., Lindgren, V., Leventhal, B.L., Courchesne, R., Lincoln, A., Shulman, C., Lord, C., Courchesne, E. (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am J Hum Genet 60, 928–34.PubMedGoogle Scholar
  138. 138.
    Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R.M., Myers, R.M., Ridker, P.M., Chasman, D. I., Mefford, H., Ying, P., Nickerson, D.A.; Eichler, E.E. (2009) Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet 84, 148–61.PubMedGoogle Scholar
  139. 139.
    Sharp, A.J., Selzer, R.R., Veltman, J.A., Gimelli, S., Gimelli, G., Striano, P., Coppola, A., Regan, R., Price, S.M., Knoers, N.V., Eis, P.S., Brunner, H.G., Hennekam, R.C., Knight, S.J., de Vries, B.B., Zuffardi, O., Eichler, E.E. (2007) Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet 16, 67–72.Google Scholar
  140. 140.
    El-Hattab, A.W., Smolarek, T.A., Walker, M.E., Schorry, E.K., Immken, L.L., Patel, G., Abbott, M.A., Lanpher, B.C., Ou, Z., Kang, S.H., Patel, A., Scaglia, F., Lupski, J.R., Cheung, S.W., Stankiewicz, P. (2009) Redefined genomic architecture in 15q24 directed by patient deletion/duplication breakpoint mapping. Hum Genet 126, 589–602.PubMedGoogle Scholar
  141. 141.
    Wat, M.J., Enciso, V.B., Wiszniewski, W., Resnick, T., Bader, P., Roeder, E.R., Freedenberg, D., Brown, C., Stankiewicz, P., Cheung, S.W., Scott, D.A. (2010) Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits, and possibly Diamond-Blackfan anemia. J Med Genet 47, 777–81.Google Scholar
  142. 142.
    Walters, R.G., Jacquemont, S., Valsesia, A., de Smith, A.J., Martinet, D., Andersson, J., Falchi, M., Chen, F., Andrieux, J., Lobbens, S., Delobel, B., Stutzmann, F., El-Sayed Moustafa, J.S., Chèvre, J.C., Lecoeur, C., Vatin, V., Bouquillon, S., Buxton, J.L., Boute, O., Holder-Espinasse, M., Cuisset, J.M., Lemaitre, M.P., Ambresin, A.E., Brioschi, A., Gaillard, M., Giusti, V., Fellmann, F., Ferrarini, A., Hadjikhani, N., Campion, D., Guilmatre, A., Goldenberg, A., Calmels, N., Mandel, J.L., Le Caignec, C., David, A., Isidor, B., Cordier, M.P., Dupuis-Girod, S., Labalme, A., Sanlaville, D., Béri-Dexheimer, M., Jonveaux, P., Leheup, B., Ounap, K., Bochukova, E.G., Henning, E., Keogh, J., Ellis, R.J., Macdermot, K.D., van Haelst, M.M., Vincent-Delorme, C., Plessis, G., Touraine, R., Philippe, A., Malan, V., Mathieu-Dramard, M., Chiesa, J., Blaumeiser, B., Kooy, R.F., Caiazzo, R., Pigeyre, M., Balkau, B., Sladek, R., Bergmann, S., Mooser, V., Waterworth, D., Reymond, A., Vollenweider, P., Waeber, G., Kurg, A., Palta, P., Esko, T., Metspalu, A., Nelis, M., Elliott, P., Hartikainen, A.L., McCarthy, M.I., Peltonen, L., Carlsson, L., Jacobson, P., Sjöström, L., Huang, N., Hurles, M.E., O’Rahilly, S., Farooqi, I.S., Männik, K., Jarvelin, M.R., Pattou, F., Meyre, D., Walley, A.J., Coin, L.J., Blakemore, A.I., Froguel, P., Beckmann, J.S. (2010) A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 463, 671–5.PubMedGoogle Scholar
  143. 143.
    Ballif, B.C., Hornor, S.A., Jenkins, E., Madan-Khetarpal, S., Surti, U., Jackson, K.E., Asamoah, A., Brock, P.L., Gowans, G.C., Conway, R.L., Graham, J.M., Medne, L., Zackai, E.H., Shaikh, T.H., Geoghegan, J., Selzer, R.R., Eis, P.S., Bejjani, B.A., Shaffer, L.G. (2007) Discovery of a previously unrecognized microdeletion syndrome of 16p11.2-p12.2. Nat Genet 39, 1071–3.PubMedGoogle Scholar
  144. 144.
    Ullmann, R., Turner, G., Kirchhoff, M., Chen, W., Tonge, B., Rosenberg, C., Field, M., Vianna-Morgante, A.M., Christie, L., Krepischi-Santos, A.C., Banna, L., Brereton, A.V., Hill, A., Bisgaard, A.M., Müller, I., Hultschig, C., Erdogan, F., Wieczorek, G., Ropers, H.H. (2007) Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat 28, 674–82.PubMedGoogle Scholar
  145. 145.
    Hannes, F.D., Sharp, A.J., Mefford, H.C., de Ravel, T., Ruivenkamp, C.A., Breuning, M.H., Fryns, J.P., Devriendt, K., Van Buggenhout, G., Vogels, A., Stewart, H.H., Hennekam, R.C., Cooper, G.M., Regan, R., Knight, S.J., Eichler, E.E., Vermeesch, J.R. (2008) Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 46, 223–32.PubMedGoogle Scholar
  146. 146.
    Mefford, H.C., Cooper, G.M., Zerr, T., Smith, J.D., Baker, C., Shafer, N., Thorland, E.C., Skinner, C., Schwartz, C.E., Nickerson, D.A., Eichler, E.E. (2009) A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Res 19, 1579–85.PubMedGoogle Scholar
  147. 147.
    Mefford, H.C., Clauin, S., Sharp, A.J., Moller, R.S., Ullmann, R., Kapur, R., Pinkel, D., Cooper, G.M., Ventura, M., Ropers, H.H., Tommerup, N., Eichler, E.E., Bellanne-Chantelot, C. (2007) Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am J Hum Genet 81, 1057–69.PubMedGoogle Scholar
  148. 148.
    Sreenath Nagamani, S.C., Erez, A., Shen, J., Li, C., Roeder, E., Cox, S., Karaviti, L., Pearson, M., Kang, S.-H.L., Sahoo, T., Lalani, S.R., Stankiewicz, P., Sutton, V.R., Cheung, SW. (2010) Clinical spectrum associated with recurrent genomic rearrangements in chromosome 17q12. Eur J Hum Genet 18, 278–84.Google Scholar
  149. 149.
    Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, Veltman JA, Brunner HG, de Vries BB. (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 38, 999–1001.PubMedGoogle Scholar
  150. 150.
    Shaw-Smith, C., Pittman, A.M., Willatt, L., Martin, H., Rickman, L., Gribble, S., Curley, R., Cumming, S., Dunn, C., Kalaitzopoulos, D., Porter, K., Prigmore, E., Krepischi-Santos, A.C., Varela, M.C., Koiffmann, C.P., Lees, A.J., Rosenberg, C., Firth, H.V., de Silva, R., Carter, N.P. (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet 38, 1032–7.PubMedGoogle Scholar
  151. 151.
    Grisart, B., Willatt, L., Destrée, A., Fryns, J.P., Rack, K., de Ravel, T., Rosenfeld, J., Vermeesch, J.R., Verellen-Dumoulin, C., Sandford, R. (2009) 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. J Med Genet 46, 524–30.PubMedGoogle Scholar
  152. 152.
    Ballif, B.C., Theisen, A., Rosenfeld, J.A., Traylor, R., Gastier-Foster, J., Thrush, L.D., Astbury, C., Bartholomew, D., McBride, K., Pyatt, R., Shane, K., Smith, W.E., Banks, V., Gallentine, W.B., Brock, P., Rudd, M.K., Adam, M.P., Keene, J.A., Phillips III, J.A., Pfotenhauer, J.P., Gowans, G.C., Stankiewicz, P., Bejjani, B.A., Shaffer, L.G. (2010) Identification of a recurrent microdeletion on 17q23.1q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities. Am J Hum Genet 86, 454–61.Google Scholar
  153. 153.
    Ben-Shachar, S., Ou, Z., Shaw, C.A., Belmont, J.W., Patel, M.S., Hummel, M., Amato, S., Tartaglia, N., Berg, J., Sutton, V.R., Lalani, S.R., Chinault, A.C., Cheung, S.W., Lupski, J.R., Patel, A. (2008) 22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome. Am J Hum Genet 82, 214–21.PubMedGoogle Scholar
  154. 154.
    Phelan, M.C. (2008) Deletion 22q13.3 syndrome. Orphanet J Rare Dis 3, 14.PubMedGoogle Scholar
  155. 155.
    Giorda, R., Bonaglia, M.C., Beri, S., Fichera, M., Novara, F., Magini, P., Urquhart, J., Sharkey, F.H., Zucca, C., Grasso, R., Marelli, S., Castiglia, L., Di Benedetto, D., Musumeci, S.A., Vitello, G.A., Failla, P., Reitano, S., Avola, E., Bisulli, F., Tinuper, P., Mastrangelo, M., Fiocchi, I., Spaccini, L., Torniero, C., Fontana, E., Lynch, S.A., Clayton-Smith, J., Black, G., Jonveaux, P., Leheup, B., Seri, M., Romano, C., dalla Bernardina, B., Zuffardi, O. (2009) Complex segmental duplications mediate a recurrent dup(X)(p11.22-p11.23) associated with mental retardation, speech delay, and EEG anomalies in males and females. Am J Hum Genet 85, 394–400.Google Scholar
  156. 156.
    Shaffer, L.G., Theisen, A., Bejjani, B.A., Ballif, B.C., Aylsworth, A.S., Lim, C., McDonald, M., Ellison, J.W., Kostiner, D., Saitta, S., Shaikh, T. (2007) The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome. Genet Med 9, 607–16.PubMedGoogle Scholar
  157. 157.
    Boland, E., Clayton-Smith, J., Woo, V.G., McKee, S., Manson, F.D., Medne, L., Zackai, E., Swanson, E.A., Fitzpatrick, D., Millen, K.J., Sherr, E.H., Dobyns, W.B., Black, G.C. (2007) Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am J Hum Genet 81, 292–303.PubMedGoogle Scholar
  158. 158.
    van Bon BW, Koolen DA, Brueton L, McMullan D, Lichtenbelt KD, Adès LC, Peters G, Gibson K, Novara F, Pramparo T, Dalla Bernardina B, Zoccante L, Balottin U, Piazza F, Pecile V, Gasparini P, Guerci V, Kets M, Pfundt R, de Brouwer AP, Veltman JA, de Leeuw N, Wilson M, Antony J, Reitano S, Luciano D, Fichera M, Romano C, Brunner HG, Zuffardi O, de Vries BB. (2010) The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur J Hum Genet 18, 163–70.PubMedGoogle Scholar
  159. 159.
    Le Meur, N., Holder-Espinasse, M., Jaillard, S., Goldenberg, A., Joriot, S., Amati-Bonneau, P., Guichet, A., Barth, M., Charollais, A., Journel, H., Auvin, S., Boucher, C., Kerckaert, J.-P., David, V., Manouvrier-Hanu, S., Saugier-Veber, P., Frébourg, T., Dubourg, C., Andrieux, J., Bonneau, D. (2009) MEF2C haploinsufficiency caused either by microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations. J Med Genet 47, 22–9.PubMedGoogle Scholar
  160. 160.
    Kleefstra, T., Brunner, H. G., Amiel, J., Oudakker, A. R., Nillesen, W. M., Magee, A., Genevieve, D., Cormier-Daire, V., van Esch, H., Fryns, J. P., Hamel, B. C. J., Sistermans, E. A., de Vries, B. B. A., van Bokhoven, H. (2006) Loss-of-function mutations in Euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum Genet 79, 370–7.PubMedGoogle Scholar
  161. 161.
    Ariani, F., Hayek, G., Rondinella, D., Artuso, R., Mencarelli, M.A., Spanhol-Rosseto, A., Pollazzon, M., Buoni, S., Spiga, O., Ricciardi, S., Meloni, I., Longo, I., Mari, F., Broccoli, V., Zappella, M., Renieri, A. (2008) FOXG1 is responsible for the congenital variant of Rett syndrome. Am J Hum Genet 83, 89–93.PubMedGoogle Scholar
  162. 162.
    Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., Nygren, G., Rastam, M., Gillberg, I. C., Anckarsater, H., Sponheim, E., Goubran-Botros, H., Delorme, R., Chabane, N., Mouren-Simeoni, M.C., de Mas, P., Bieth, E., Rogé, B., Héron, D., Burglen, L., Gillberg, C., Leboyer, M., Bourgeron, T. (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39, 25–7.PubMedGoogle Scholar
  163. 163.
    Wang, J., Killinger, D. W., Hegele, R. A. (1999) A microdeletion within DAX-1 in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism. J Invest Med 47, 232–5.Google Scholar
  164. 164.
    Bardoni, B., Zanaria, E., Guioli, S., Floridia, G., Worley, K.C., Tonini, G., Ferrante, E., Chiumello, G., McCabe, E.R., Fraccaro, M., Zuffardi, O.,  Camerino, G. (1994) A dosage sensitive locus at chromosome Xp21 is involved in male to female sex reversal. Nat Genet 7, 497–501.PubMedGoogle Scholar
  165. 165.
    Li, L., Krantz, I. D., Deng, Y., Genin, A., Banta, A. B., Collins, C. C., Qi, M., Trask, B. J., Kuo, W. L., Cochran, J., Costa, T., Pierpont, M.E., Rand, E.B., Piccoli, D. A., Hood, L., Spinner, N. B. (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16, 243–51.PubMedGoogle Scholar
  166. 166.
    Garg, V., Kathiriya, I. S., Barnes, R., Schluterman, M. K., King, I. N., Butler, C. A., Rothrock, C. R., Eapen, R. S., Hirayama-Yamada, K., Joo, K., Matsuoka, R., Cohen, J. C., Srivastava, D. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424, 443–7.PubMedGoogle Scholar
  167. 167.
    Shimkets, R., Gailani, M. R., Siu, V. M., Yang-Feng, T., Pressman, C. L., Levanat, S., Goldstein, A., Dean, M., Bale, A. E. (1996) Molecular analysis of chromosome 9q deletions in two Gorlin syndrome patients. Am J Hum Genet 59, 417–22.PubMedGoogle Scholar
  168. 168.
    Chang, E.H., Menezes, M., Meyer, N.C., Cucci, R.A., Vervoort, V.S., Schwartz, C.E., Smith, R.J. (2004) Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat 23, 582–9.PubMedGoogle Scholar
  169. 169.
    Hellemans, J., Preobrazhenska, O., Willaert, A., Debeer, P., Verdonk, P. C. M., Costa, T., Janssens, K., Menten, B., Van Roy, N., Vermeulen, S. J. T., Savarirayan, R., Van Hul, W., Vanhoenacker, F., Huylebroeck, D., De Paepe, A., Naeyaert, J.M., Vandesompele, J., Speleman, F., Verschueren, K., Coucke, P.J., Mortier, G.R. (2004) Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. Nat Genet 36, 1213–8.PubMedGoogle Scholar
  170. 170.
    Wagner, T., Wirth, J., Meyer, J., Zabel, B., Held, M., Zimmer, J., Pasantes, J., Dagna Bricarelli, F., Keutel, J., Hustert, E., Wolf, U., Tommerup, N., Schempp, W., Scherer, G. (1994) Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111–20.PubMedGoogle Scholar
  171. 171.
    McDermid, H.E., Duncan, A.M.V., Brasch, K.R., Holden, J.J.A., Magenis, E., Sheehy, R., Burn, J., Kardon, N., Noel, B., Schinzel, A., Teshima, I., White, B.N. (1986) Characterization of the supernumerary chromosome in cat eye syndrome. Science 232, 646–8.PubMedGoogle Scholar
  172. 172.
    Mundlos, S., Otto, F., Mundlos, C., Mulliken, J.B., Aylsworth, A.S., Albright, S., Lindhout, D., Cole, W.G., Henn, W., Knoll, J.H.M., Owen, M.J., Mertelsmann, R., Zabel, B.U., Olsen, B.R. (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773–9.PubMedGoogle Scholar
  173. 173.
    Klaassens, M., van Dooren, M., Eussen, H.J., Douben, H., den Dekker, A.T., Lee, C., Donahoe, P.K., Galjaard, R.J., Goemaere, N., de Krijger, R.R., Wouters, C., Wauters, J., Oostra, B.A., Tibboel, D., de Klein, A. (2005) Congenital diaphragmatic hernia and chromosome 15q26: determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization. Am J Hum Genet 76, 877–82.PubMedGoogle Scholar
  174. 174.
    Nelen, M.R., van Staveren, W.C.G., Peeters, E.A.J., Ben Hassel, M., Gorlin, R.J., Hamm, H., Lindboe, C.F., Fryns, J.-P., Sijmons, R.H., Woods, D.G., Mariman, E.C.M., Padberg, G.W., Kremer, H. (1997) Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6, 1383–7.PubMedGoogle Scholar
  175. 175.
    Mainardi, P.C., Perfumo, C., Cali, A., Coucourde, G., Pastore, G., Cavani, S., Zara, F., Overhauser, J., Pierluigi, M., Bricarelli, F.D. (2001) Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation. J Med Genet 38, 151–8.PubMedGoogle Scholar
  176. 176.
    Belloni E, Martucciello G, Verderio D, Ponti E, Seri M, Jasonni V, Torre M, Ferrari M, Tsui LC, Scherer SW. (2000) Involvement of the HLXB9 homeobox gene in Currarino syndrome. Am J Hum Genet 66, 312–9PubMedGoogle Scholar
  177. 177.
    Kohlhase, J., Heinrich, M., Schubert, L., Liebers, M., Kispert, A., Laccone, F., Turnpenny, P., Winter, R.M., Reardon, W. (2002) Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet 11, 2979–87.PubMedGoogle Scholar
  178. 178.
    den Dunnen, J.T., Grootscholten, P.M., Bakker, E., Blonden, L.A.J., Ginjaar, H.B., Wapenaar, M.C., van Paassen, H.M.B., van Broeckhoven, C., Pearson, P.L., van Ommen, G.J.B. (1989) Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications. Am J Hum Genet 45, 835–47.Google Scholar
  179. 179.
    Erez, A., Patel, A. J., Wang, X., Xia, Z., Bhatt, S. S., Craigen, W., Cheung, S. W., Lewis, R. A., Fang, P., Davenport, S. L. H., Stankiewicz, P., Lalani, S. R. (2009) Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder. Neurogenetics 10, 363–9.PubMedGoogle Scholar
  180. 180.
    Wang, X., Reid Sutton, V., Omar Peraza-Llanes, J., Yu, Z., Rosetta, R., Kou, Y.C., Eble, T.N., Patel, A., Thaller, C., Fang, P., Van den Veyver, I.B. (2007) Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet 39, 836–8.PubMedGoogle Scholar
  181. 181.
    Grzeschik, K.H., Bornholdt, D., Oeffner, F., König, A., del Carmen Boente, M., Enders, H., Fritz, B., Hertl, M., Grasshoff, U., Höfling, K., Oji, V., Paradisi, M., Schuchardt, C., Szalai, Z., Tadini, G., Traupe, H., Happle, R. (2007) Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nat Genet 39, 833–5.PubMedGoogle Scholar
  182. 182.
    Vortkamp, A., Gessler, M., Grzeschik, K.-H. (1991) GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–40.PubMedGoogle Scholar
  183. 183.
    Basson, C. T., Bachinsky, D. R., Lin, R. C., Levi, T., Elkins, J. A., Soults, J., Grayzel, D., Kroumpouzou, E., Traill, T. A., Leblanc-Straceski, J., Renault, B., Kucherlapati, R., Seidman, J. G., Seidman, C. E. (1997) Mutations in human cause limb and cardiac malformation in Holt-Oram syndrome. Nat Genet 15, 30–5.PubMedGoogle Scholar
  184. 184.
    Van Esch, H., Groenen, P., Nesbit, M.A., Schuffenhauer, S., Lichtner, P., Vanderlinden, G., Harding, B., Beetz, R., Bilous, R.W., Holdaway, I., Shaw, N.J., Fryns, J.P., Van de Ven, W., Thakker, R.V., Devriendt, K. (2000) GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406, 419–22.PubMedGoogle Scholar
  185. 185.
    Coldren, C.D., Lai, Z., Shragg, P., Rossi, E., Glidewell, S.C., Zuffardi, O., Mattina, T., Ivy, D.D., Curfs, L.M., Mattson, S.N., Riley, E.P., Treier, M., Grossfeld, P.D. (2009) Chromosomal microarray mapping suggests a role for BSX and neurogranin in neurocognitive and behavioral defects in the 11q terminal deletion disorder (Jacobsen syndrome). Neurogenetics 10, 89–95.PubMedGoogle Scholar
  186. 186.
    Ballabio, A., Parenti, G., Tippett, P., Mondello, C., Di Maio, S., Tenore, A., Andria,G. (1986) X-linked ichthyosis, due to steroid sulphatase deficiency, associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia): linkage relationships with Xg and cloned DNA sequences from the distal short arm of the X chromosome. Hum Genet 72, 237–40.PubMedGoogle Scholar
  187. 187.
    Ludecke, H. J., Schaper, J., Meinecke, P., Momeni, P., Gross, S., von Holtum, D., Hirche, H., Abramowicz, M. J., Albrecht, B., Apacik, C., Christen, H. J., Claussen, U Devriendt, K., Fastnacht, E., Forderer, A., Friedrich, U., Goodship, T.H., Greiwe, M., Hamm, H., Hennekam, R.C., Hinkel, G.K., Hoeltzenbein, M., Kayserili, H., Majewski, F., Mathieu, M., McLeod, R., Midro, A.T., Moog, U., Nagai, T., Niikawa, N., Orstavik, K.H., Plöchl, E., Seitz, C., Schmidtke, J., Tranebjaerg, L., Tsukahara, M., Wittwer, B., Zabel, B., Gillessen-Kaesbach, G., Horsthemke, B. (2001) Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III. Am J Hum Genet 68, 81–91.Google Scholar
  188. 188.
    Rao, E., Weiss, B., Fukami, M., Rump, A., Niesler, B., Mertz, A., Muroya, K., Binder, G., Kirsch, S., Winkelmann, M., Nordsiek, G., Heinrich, U., Breuning, M.H., Ranke, M.B., Rosenthal, A., Ogata, T., Rappold, G.A. (1997) Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 16, 54–63.PubMedGoogle Scholar
  189. 189.
    Benito-Sanz, S., Gorbenko del Blanco, D., Huber, C., Thomas, N.S., Aza-Carmona, M., Bunyan, D., Maloney, V., Argente, J., Cormier-Daire, V., Campos-Barros, A., Heath, K.E. (2006) Characterization of SHOX deletions in Leri-Weill Dyschondrosteosis (LWD) reveals genetic heterogeneity and no recombination hotspots. Am J Hum Genet 79, 409–14.PubMedGoogle Scholar
  190. 190.
    des Portes, V., Pinard, J.M., Billuart, P., Vinet, M.C., Koulakoff, A., Carrie, A., Gelot, A., Dupuis, E., Motte, J., Berwald-Netter, Y., Catala, M., Kahn, A., Beldjord, C., Chelly, J. (1998) A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92, 51–61.Google Scholar
  191. 191.
    Gleeson, J.G., Allen, K.M., Fox, J.W., Lamperti, E.D., Berkovic, S., Scheffer, I., Cooper, E.C., Dobyns, W.B., Minnerath, S.R., Ross, M.E., Walsh, C.A. (1998) Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92, 63–72.PubMedGoogle Scholar
  192. 192.
    Lubs, H., Abidi, F., Bier, J. A. B., Abuelo, D., Ouzts, L., Voeller, K., Fennell, E., Stevenson, R. E., Schwartz, C. E., Arena, F. (1999) XLMR syndrome characterized by multiple respiratory infections, hypertelorism, severe CNS deterioration and early death localizes to distal Xq28. Am J Med Genet 85, 243–8.PubMedGoogle Scholar
  193. 193.
    Schinzel, A. (1988) Microdeletion syndromes, balanced translocations, and gene mapping. J Med Genet 25, 454–62.PubMedGoogle Scholar
  194. 194.
    Amiel, J., Espinosa-Parrilla, Y., Steffann, J., Gosset, P., Pelet, A., Prieur, M., Boute, O., Choiset, A., Lacombe, D., Philip, N., Le Merrer, M., Tanaka, H., Till, M., Touraine, R., Toutain, A., Vekemans, M., Munnich, A., Lyonnet, S. (2001) Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures. Am J Hum Genet 69, 1370–7.PubMedGoogle Scholar
  195. 195.
    Dreyer, S. D., Zhou, G., Baldini, A., Winterpacht, A., Zabel, B., Cole, W., Johnson, R. L., Lee, B. (1998) Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 19, 47–50.PubMedGoogle Scholar
  196. 196.
    Asthagiri, A.R., Parry, D.M., Butman, J.A., Kim, H.J., Tsilou, E.T., Zhuang, Z., Lonser, R.R. 2009. Neurofibromatosis type 2. Lancet 373, 1974–86.PubMedGoogle Scholar
  197. 197.
    Rodriguez-Revenga, L., Madrigal, I., Alkhalidi, L.S., Armengol, L., González, E., Badenas, C., Estivill, X., Milà, M. (2007) Contiguous deletion of the NDP, MAOA, MAOB, and EFHC2 genes in a patient with Norrie disease, severe psychomotor retardation and myoclonic epilepsy. Am J Med Genet A 143, 916–20.Google Scholar
  198. 198.
    Ferrentino, R., Bassi, M.T., Chitayat, D., Tabolacci, E., Meroni, G. (2007) MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified. Hum Mutat 28, 206–7.PubMedGoogle Scholar
  199. 199.
    Tuchman, M., Plante, R.J., Garcia-Perez, M.A., Rubio, V. (1996) Relative frequency of mutations causing ornithine transcarbamylase deficiency in 78 families. Hum Genet 97, 274–6.PubMedGoogle Scholar
  200. 200.
    Schinzel, A. (1991) Tetrasomy 12p (Pallister-Killian syndrome). J Med Genet 28, 122–5.PubMedGoogle Scholar
  201. 201.
    Polymeropoulos, M. H., Higgins, J. J., Golbe, L. I., Johnson, W. G., Ide, S. E., Di Iorio, G., Sanges, G., Stenroos, E. S., Pho, L. T., Schaffer, A. A., Lazzarini, A. M., Nussbaum, R. L., Duvoisin, R. C. (1996) Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 274, 1197–8.PubMedGoogle Scholar
  202. 202.
    Inoue K. (2005) PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6, 1–16.PubMedGoogle Scholar
  203. 203.
    Zweier, C., Peippo, M. M., Hoyer, J., Sousa, S., Bottani, A., Clayton-Smith, J., Reardon, W., Saraiva, J., Cabral, A., Gohring, I., Devriendt, K., de Ravel, T., Bijlsma, E. K., Hennekam, R. C., M., Orrico, A., Cohen, M., Dreweke, A., Reis, A., Nurnberg, P., Rauch, A. (2007) Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet 80, 994–1001.Google Scholar
  204. 204.
    Potocki, L., Shaffer, L. G. (1996) Interstitial deletion of 11(p11.2p12): a newly described contiguous gene deletion syndrome involving the gene for hereditary multiple exostoses (EXT2). Am J Med Genet 62, 319–25.PubMedGoogle Scholar
  205. 205.
    Zhu, X., Dunn, J. M., Phillips, R. A., Goddard, A. D., Paton, K. E., Becker, A., Gallie, B. L. (1989) Preferential germline mutation of the paternal allele in retinoblastoma. Nature 340, 312–3.PubMedGoogle Scholar
  206. 206.
    Moog, U., Smeets, E.E.J., van Roozendaal, K.E.P., Schoenmakers, S., Herbergs, J., Schoonbrood-Lenssen, A.M.J., Schrander-Stumpel, C.T.R.M. (2003) Neuro­developmental disorders in males related to the gene causing Rett syndrome in females (MECP2). Eur J Paediat Neurol 7, 5–12.Google Scholar
  207. 207.
    Petrij, F., Dauwerse, H. G., Blough, R. I., Giles, R. H., van der Smagt, J. J., Wallerstein, R., Maaswinkel-Mooy, P. D., van Karnebeek, C. D., van Ommen, G.-J. B., van Haeringen, A., Rubinstein, J. H., Saal, H. M., Hennekam, R. C. M., Peters, D. J. M., Breuning, M. H. (2000) Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. J Med Genet 37, 168–76.PubMedGoogle Scholar
  208. 208.
    El Ghouzzi, V., Le Merrer, M., Perrin-Schmitt, F., Lajeunie, E., Benit, P., Renier, D., Bourgeois, P., Bolcato-Bellemin, A.-L., Munnich, A., Bonaventure, J. (1997) Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet 15, 42–46.PubMedGoogle Scholar
  209. 209.
    Scherer, S.W., Poorkaj, P., Allen, T., Kim, J., Geshuri, D., Nunes, M., Soder, S., Stephens, K., Pagon, R.A., Patton, M.A., et al. (1994) Fine mapping of the autosomal dominant split hand/split foot locus on chromosome 7, band q21.3-q22.1. Am J Hum Genet 55, 12–20.PubMedGoogle Scholar
  210. 210.
    de Mollerat, X.J., Gurrieri, F., Morgan, C.T., Sangiorgi, E., Everman, D.B., Gaspari, P., Amiel, J., Bamshad, M.J., Lyle, R., Blouin, J.L., Allanson, J.E., Le Marec, B., Wilson, M., Braverman, N.E., Radhakrishna, U., Delozier-Blanchet, C., Abbott, A., Elghouzzi, V., Antonarakis, S., Stevenson, R.E., Munnich, A., Neri, G., Schwartz, C.E. (2003) A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24. Hum Mol Genet 12, 1959–71.PubMedGoogle Scholar
  211. 211.
    Kohlhase, J., Wischermann, A., Reichenbach, H., Froster, U., Engel, W. (1998) Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18, 81–3.PubMedGoogle Scholar
  212. 212.
    Brook-Carter, P.T., Peral, B., Ward, C.J., Thompson, P., Hughes, J., Maheshwar, M.M., Nellist, M., Gamble, V., Harris, P.C., Sampson, J.R. (1994) Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease: a contiguous gene syndrome. Nat Genet 8, 328–32.PubMedGoogle Scholar
  213. 213.
    Jones, A. C., Daniells, C. E., Snell, R.G., Tachataki, M., Idziaszczyk, S.A., Krawczak, M., Sampson, J.R., Cheadle, J.P. (1997) Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Molec Genet 6, 2155–61.PubMedGoogle Scholar
  214. 214.
    Klopocki, E., Neumann, L. M., Tonnies, H., Ropers, H.-H., Mundlos, S., Ullmann, R. (2006) Ulnar-mammary syndrome with dysmorphic facies and mental retardation caused by a novel 1.28 Mb deletion encompassing the TBX3 gene. Eur J Hum Genet 14, 1274–9.PubMedGoogle Scholar
  215. 215.
    Kondo, S., Schutte, B.C., Richardson, R.J., Bjork, B. C., Knight, A.S., Watanabe, Y., Howard, E., Ferreira de Lima, R.L.L., Daack-Hirsch, S., Sander, A., McDonald-McGinn, D. M., Zackai, E.H., Lammer, E.J., Aylsworth, A.S., Ardinger, H.H., Lidral, A.C., Pober, B.R., Moreno, L., Arcos-Burgos, M., Valencia, C., Houdayer, C., Bahuau, M., Moretti-Ferreira, D., Richieri-Costa, A., Dixon, M.J., Murray, J.C. (2002) Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32, 285–9.PubMedGoogle Scholar
  216. 216.
    Zollino, M., Lecce, R., Fischetto, R., Murdolo, M., Faravelli, F., Selicorni, A., Buttè, C., Memo, L., Capovilla, G., Neri, G. (2003) Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72, 590–7.PubMedGoogle Scholar
  217. 217.
    Kato, M., Das, S., Petras, K., Kitamura, K., Morohashi, K., Abuelo, D.N., Barr, M., Bonneau, D.,,Brady, A.F., Carpenter, N.J., Cipero, K.L., Frisone, F., Fukuda, T., Guerrini, R., Iida, E., Itoh, M., Lewanda, A.F., Nanba, Y., Oka, A., Proud, V.K., Saugier-Veber, P., Schelley, S.L., Selicorni, A., Shaner, R., Silengo, M., Stewart, F., Sugiyama, N., Toyama, J., Toutain, A., Vargas, A.L., Yanazawa, M., Zackai, E.H., Dobyns, W.B. (2004) Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum Mutat 23, 147–59.PubMedGoogle Scholar
  218. 218.
    Sumegi, J., Huang, D., Lanyi, A., Davis, J.D., Seemayer, T.A., Maeda, A., Klein, G., Seri, M., Wakiguchi, H., Purtilo, D.T., Gross, T.G. (2000) Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood 96, 3118–25.PubMedGoogle Scholar
  219. 219.
    Zhang, Y.H., Huang, B.L., Niakan, K.K., McCabe, L.L., McCabe, E.R., Dipple, K.M. (2004) IL1RAPL1 is associated with mental retardation in patients with complex glycerol kinase deficiency who have deletions extending telomeric of DAX1. Hum Mutat 24, 273.PubMedGoogle Scholar
  220. 220.
    Laumonnier, F., Ronce, N., Hamel, B.C., Thomas, P., Lespinasse, J., Raynaud, M., Paringaux, C., Van Bokhoven, H., Kalscheuer, V., Fryns, J.P., Chelly, J., Moraine, C., Briault, S. (2002) Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. Am J Hum Genet 71, 1450–5.PubMedGoogle Scholar
  221. 221.
    Najm, J., Horn, D., Wimplinger, I., Golden, J.A., Chizhikov, V.V., Sudi, J., Christian, S.L., Ullmann, R., Kuechler, A., Haas, C.A., Flubacher, A., Charnas, L.R., Uyanik, G., Frank, U., Klopocki, E., Dobyns, W.B., Kutsche, K. (2008) Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 40, 1065–7.PubMedGoogle Scholar
  222. 222.
    Girirajan, S., Campbell, C.D., Eichler, E. E. (2011) Human copy number variation and complex genetic disease. Annu Rev Genet 45, 203–26.PubMedGoogle Scholar
  223. 223.
    Ramocki, M..B., Bartnik, M., Szafranski, P., Kołodziejska, K. E., Xia, Z., Bravo, J., Miller, G. S., Rodriguez, D.L., Williams, C.A., Bader, P.I., Szczepanik, E., Mazurczak, T., Antczak-Marach, D., Coldwell, J.G., Akman, C.I., McAlmon, K., Cohen, M.P., McGrath, J., Roeder, E., Mueller, J., Kang, S.-H., Bacino, C. A., Patel, A., Bocian, E., Shaw, C. A., Cheung, S. W., Mazurczak, T., Stankiewicz, P. (2010) Recurrent Distal 7q11.23 Deletion Including HIP1 and YWHAG Identified in Patients with Intellectual Disabilities, Epilepsy, and Neurobehavioral Problems. Am J Hum Genet 87, 857–65.PubMedGoogle Scholar
  224. 224.
    Stankiewicz, P., Kulkarni, S., Dharmadhikari, A. V., Sampath, S., Bhatt, S. S., Shaikh, T. H., Xia, Z., Pursley, A.N., Cooper, M. L., Shinawi, M., Paciorkowski, A. R., Grange, D. K., Noetzel, M. J., Saunders, S., Simons, P., Summar, M., Lee, B., Scaglia, F., Fellmann, F., Martinet, D., Beckmann, J. S., Asamoah, A., Platky, K., Sparks, S., Martin, A. S., Madan-Khetarpal, S., Hoover, J., Medne, L., Bonnemann, C.G., Moeschler, J. B., Vallee, S. E., Parikh, S., Irwin, P., Dalzell, V. P., Smith, W. E., Banks, V. C., Flannery, D. B., Lovell, C. M., Bellus, G. A., Golden-Grant, K., Gorski, J. L., Kussmann, J. L., McGregor, T. L., Hamid, R., Pfotenhauer, J., Ballif, B.C., Shaw, C. A., Kang, S.-H., Bacino, C. A., Patel, A., Rosenfeld, J. A., Cheung, S. W., Shaffer, L. G. (2011) Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats. Hum Mutat In press. PubMedGoogle Scholar
  225. 225.
    Dimitrov, B., Balikova, I., de Ravel, T., Van Esch, H., De Smedt, M., Baten, E., Vermeesch, J. R., Bradinova, I., Simeonov, E., Devriendt, K., Fryns, J. P., Debeer, P. (2011) 2q31.1 microdeletion syndrome: redefining the associated clinical phenotype. J Med Genet 48, 98–104.PubMedGoogle Scholar
  226. 226.
    Palomares, M., Delicado, A., Mansilla, E., de Torres, M. L., Vallespín, E., Fernandez, L., Martinez-Glez, V., García-Miñaur, S., Nevado, J., Simarro, F. S., Ruiz-Perez, V. L., Lynch, S. A., Sharkey, F. H., Thuresson, A. C., Annerén, G., Belligni, E. F., Martínez-Fernández, M. L., Bermejo, E., Nowakowska, B., Kutkowska-Kazmierczak, A., Bocian, E., Obersztyn, E., Martínez-Frías, M. L., Hennekam, R. C., Lapunzina, P. (2011) Characterization of a 8q21.11 microdeletion syndrome associated with intellectual disability and a recognizable phenotype. Am J Hum Genet 89, 295–301.PubMedGoogle Scholar
  227. 227.
    de Kovel, C.G., Trucks, H., Helbig, I., Mefford, H.C., Baker, C., Leu, C., Kluck, C., Muhle, H., von Spiczak, S., Ostertag, P., Obermeier, T., Kleefuss-Lie, A.A., Hallmann, K., Steffens, M., Gaus, V., Klein, K.M., Hamer, H.M., Rosenow, F., Brilstra, E.H., Trenité, D.K., Swinkels, M.E., Weber, Y.G., Unterberger, I., Zimprich, F., Urak, L., Feucht, M., Fuchs, K., Møller, R.S., Hjalgrim, H., De Jonghe, P., Suls, A., Rückert, I.M., Wichmann, H.E., Franke, A., Schreiber, S., Nürnberg, P., Elger, C.E., Lerche, H., Stephani, U., Koeleman, B.P., Lindhout, D., Eichler, E.E., Sander, T. (2010) Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133, 23–32.PubMedGoogle Scholar
  228. 228.
    Nagamani, S.C., Erez, A., Bay, C., Pettigrew, A., Lalani, S.R., Herman, K., Graham, B.H., Nowaczyk, M.J., Proud, M., Craigen, W.J., Hopkins, B., Kozel, B., Plunkett, K., Hixson, P., Stankiewicz, P., Patel, A., Cheung, S.W. (2011) Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43–q44. Eur J Hum Genet in press.PubMedGoogle Scholar
  229. 229.
    Ballif, B.C., Rosenfeld, J.A., Traylor, R., Theisen, A., Bader, P.I., Ladda, R.L., Sell, S.L., Steinraths, M., Surti, U., McGuire, M., Williams, S., Farrell, S.A., Filiano, J., Schnur, R.E., Coffey, L.B., Tervo, R.C., Stroud, T., Marble, M., Netzloff, M., Hanson, K., Aylsworth, A.S., Bamforth, J.S., Babu, D., Niyazov, D.M., Ravnan, J.B., Schultz, R.A., Lamb, A.N., Torchia, B.S., Bejjani, B.A., Shaffer, L.G. (2011) High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44. Hum Genet in press.PubMedGoogle Scholar
  230. 230.
    Cho, T.-J., Kim, O.-H., Choi, I. H., Nishimura, G., Superti-Furga, A., Kim, K. S., Lee, Y.-J., Park, W.-Y. (2010) A dominant mesomelic dysplasia associated with a 1.0-Mb microduplication of HOXD gene cluster at 2q31.1. J Med Genet 47, 638–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Lisenka E. L. M. Vissers
    • 1
  • Paweł Stankiewicz
    • 2
    • 3
  1. 1.Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Nijmegen Centre for Molecular Life SciencesRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  2. 2.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  3. 3.Department of Medical GeneticsInstitute of Mother and ChildWarsawPoland

Personalised recommendations